The long term goal of our research is to understand and manipulate immune surveillance pathways. The antigen processing mechanisms yields thousands of peptide/MHC complexes (pMHC I and pMHC II) on the cell surface as potential ligands for CD8+ and CD4+ T cells respectively. With prior funding support we showed that antigenic peptides are trimmed not only in the cytoplasm, but also in the endoplasmic reticulum by ERAAP, the ER aminopeptidase associated with antigen processing. This key concept is now part of current text book descriptions of antigen processing pathways. In ERAAP-deficient mice, lack of peptide trimming in the ER has been found to disrupt the normal peptide repertoire by both classic MHC Ia as well as non-classical MHC Ib molecules: many pMHC I are missing and numerous novel pMHC I emerge on the surface of ERAAP-deficient cells. The loss and gain of unique peptides results in vigorous reciprocal immune responses in wild-type versus ERAAP-deficient mice. We have also discovered that ERAAP and MHC I interact physically and functionally and truncated ERAAPdomains serve as dominant negative regulators of MHC I peptide presentation. Unexpectedly, we also discovered that ERAAP can also regulate peptide presentation by MHC class II molecules and hence CD4 T cell responses as well. These properties of ERAAP may explain the recent genome wide association studies that have shown that polymorphic variants of ERAP1 (human ortholog of mouse ERAAP) are associated with autoimmune diseases such as ankylosing spondylitis and psoriasis. Here we will test the molecular mechanisms and consequences of ERAAP's role in regulating the peptide repertoires presented by MHC I and MHC II molecules. We will also test the hypothesis that ERAAP polymorphisms influence the peptide presentation by particular MHC molecules that could cause normally tolerated self-peptides to become immunogenic and thus cause autoimmunity. We anticipate the results to provide new insights into the antigen processing pathways and how these pathways could be manipulated to regulate immunogenicity and presently incurable autoimmune disorders.